This revised application is a competing continuation of MH-R01 57102, Postpartum Depression: Nortriptyline vs. Sertraline. The period of funding was from 04/01/1997 - 03/31/2003, with a no-cost extension through 03/31/2004. The proposed grant is being submitted as a competing continuation because it is built directly upon findings from the program of research delineated in the original grant. The original study was a randomized clinical trial of the tricyclic antidepressant nortriptyline (NTP) compared to the selective serotonin reuptake inhibitor sertraline (SERT) for postpartum major depression (PPMD). The major finding was that NTP was equivalent to SERT on all outcome measures. Antidepressant therapy with NTP and SERT were efficacious for PPMD after one month of treatment, with minimal gains thereafter. Responders to SERT had a significantly more rapid symptomatic decline than responders to NTP. We concluded that comparing additional antidepressants for PPMD has less potential public health impact than advancing our therapeutic armamentarium by evaluating the efficacy of estradiol (E2) therapy for PPMD, which has received minimal research attention in America. The design is an 8 week randomized double-blind clinical trial of SERT vs. E2 vs. Placebo. Responders enter a continuation phase with the blind intact through 6.5 months postpartum. The primary aims of this investigation are to: 1) Test the efficacy of E2 compared to placebo for the treatment of PPMD. Sertraline will be included as an active comparator. We have powered the study to test for differences among the three groups and also test for differences between the E2 and placebo group. We will test the hypothesis that E2 will be significantly more effective than placebo and that SERT will be significantly more effective than placebo. 2) Evaluate developmental outcomes in infants exposed to the disorder, PPMD, and the medications (SERT, exogenous E2 or Placebo) which may be transmitted to the infants through breastfeeding. All infants in this study will have exposure to mothers with depression. We will assess maternal depression, mother-infant serum SERT and E2 levels and relate them to mother-infant interactional quality and infant developmental outcomes on the Bayley Scales of Infant Development. These data will enhance the sophistication of risk-benefit analyses for pharmacotherapy during lactation. Exploratory aims are to: 1) evaluate the durability of responses to E2, SERT, and Placebo;2) identify correlates of response and remission to SERT, E2 and Placebo;3) explore the relationship of response and/or remission in both the E2, SERT and PL-treated groups to: (serum E2 levels at response-serum E2 levels at baseline) and (serum E2 levels at response);and 4) examine intercorrelations across time and measures with structural equation modeling to build a model that elucidates the relationship between maternal symptoms, maternal functional levels and infant outcomes.